title: Novel Gemini vitamin D(3) analogs have potent antitumor activity.
abstract: The active form of vitamin D(3), 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], modulates proliferation and induces differentiation of many cancer cells. A new class of analogs of vitamin D(3) has been synthesized, having two side-chains attached to carbon-20 (Gemini) and deuterium substituted on one side-chain. We have examined six of these analogs for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP, PC-3, DU145), lung (H520), colon (HT-29), and breast (MCF-7) cancer cell lines. Dose-response clonogenic studies showed that all six analogs had greater antiproliferative activities against cancer cells than 1,25(OH)(2)D(3). Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 1,25(OH)(2)D(3) in causing 50% clonal growth inhibition (ED(50)) of HL-60 cells. Pulse-exposure studies demonstrated that exposure to BXL-01-120 (10(-9)M, 48h) resulted in 85% clonal inhibition of HL-60 growth. BXL-01-0120 (10(-11)M, 4 days) induced the differentiation marker, CD11b. Also, morphologically differentiation was more prominent compared to 1,25(OH)(2)D(3). Annexin V assay showed that BXL-01-0120 (10(-10)M, 4 days) induced significantly (p<0.05) more apoptosis than 1,25(OH)(2)D(3). In summary, these analogs have a unique structure resulting in extremely potent inhibition of clonal proliferation of various types of cancer cells, especially HL-60 cells.
authors.affiliation: Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.
authors.forename: Tsuyako
authors.initials: T
authors.lastname: Saito
authors.forename: Ryoko
authors.initials: R
authors.lastname: Okamoto
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: James
authors.initials: J
authors.lastname: O'Kelly
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Marczak
authors.forename: Pawel
authors.initials: P
authors.lastname: Jankowski
authors.forename: Riem
authors.initials: R
authors.lastname: Badr
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D002762:Cholecalciferol